Host-adapted metabolism of Staphylococcus aureus Small-Colony Variants

金黄色葡萄球菌（Staphylococcus aureus）小菌落变异（scv）是一种表型亚群，专门适应于细胞内的生活方式，通常导致慢性持续性，通常治疗难治性感染的临床过程。首次研究了天然的临床衍生SCV的代谢，表明表型开关相关的代谢改变比迄今为止使用的定义的电子传递链中断SCV模拟突变所反映的更为复杂。与具有正常表型的亲本菌株相比，我们将研究病原体对细胞内生活方式的代谢和生理适应(i)通过全基因组测定SCV表型形成过程中假定的遗传改变和（ii）通过非蛋白质编码调节rna对表型形成的影响的功能分析。在描述金黄色葡萄球菌内化到宿主细胞和细胞内持久性的同时，还将分析宿主细胞的反应。代谢和生理变化将通过蛋白质组学和生物分析（同位素）方法进行分析。特别是，将开发用于启动实验引发的双向表型开关的体内模型，以(i)追踪和表征与表型开关相关的代谢变化，（ii）实验记录其对感染临床过程的影响，从而开辟影响治疗性急性和慢性金黄色葡萄球菌感染的替代方法。

Staphylococcus aureus small-colony variants (SCVs) represent a phenotypic subpopulation specifically adapted for an intracellular life style and typically leading to the clinical course of chronic-persistent, often therapy-refractory infections. For the first time, the metabolism of a natural, clinically derived SCV was investigated showing that phenotype switch-related metabolic alterations are more complex than reflected by defined electron transport chain-interrupting SCV-mimicking mutants used hitherto. In comparison to parental strains with normal phenotype, we will investigate the pathogen´s metabolic and physiological adaption onto the intracellular lifestyle (i) by genome-wide determination of putative genetic alterations in the course of the SCV phenotype formation and (ii) by functional analysis of the impact of non-protein coding regulatory RNAs on the phenotype formation. In parallel to the characterization of the S. aureus internalization into host cells and intracellular persistence, the host cell response will be analyzed. Metabolic and physiological changes will be analyzed by proteomic and bioanalytical (isotopologue) approaches. In particular, in vivo models for initiation of an experimentally provoked bidirectional phenotype switch will be developed to (i) trace and characterize the phenotype switch-related metabolic changes and (ii) to document experimentally their consequences on the clinical course of an infection and, thus, opening up alternative ways to influence therapeutically acute and chronic S. aureus infections.